Our long-term goal is to understand the mechanisms that control the growth, differentiation, and regeneration of the liver. Epidermal growth factor (EGF) and its homologs are the most thoroughly studied growth factors in the control of liver growth, regeneration and carcinogenesis. However, the relationship of EGF to the liver is complex, since we now know that there are multiple EGF-like molecules and that they act through four different receptors, the ErbB proteins. Signaling by ErbB tyrosine kinases depends on not only which ligands are present, but also which combinations of receptors are recruited into signaling complexes. There are also negative regulators of ErbB signaling, such as tyrosine phosphatases and proteins, such as Ralt, that complex directly with the ErbB proteins. This analysis is also complicated by the role of other receptors that interact with the ErbB proteins, including c-Met, the receptor for HGF. We and others have shown that c-met requires a functional EGF receptor to elicit its effects on motility and mitogenesis. This grant focuses on the role played by the ErbB receptors as regulators of growth and differentiation in the liver. We have created hepatocyte- specific EGFr, ErbB2, and ErbB3 deficient mice by gene targeting, and have obtained liver-specific c-Met gene deleted mice. The specific aims of this proposal are to: 1) To define the interactions among the ErbB proteins and c-Met in the mitogenic signaling of the normal and regenerating liver; 2) To evaluate the central role of the ErbB proteins as signal transducers of HGF. Progress toward these aims will improve our understanding of how EGF-like molecules signal in a normal tissue, how the liver differentiates into its adult functional form, and how these potent mitogens regulate the dramatic restoration of liver mass during regeneration. Liver regeneration is a paradigm for other conditions of normal or altered growth regulation, including tissue hypertrophy, wound healing, and cancer. In addition to elucidating the mechanisms of growth control in the liver, our studies may ultimately aid in the generation of mature hepatocytes from undifferentiated cells for transplantation and for the generation of artificial livers. PUBLIC HEALTH RELEVANCE. Liver failure inevitably results in death unless the patient can be medically supported long enough to allow the damaged liver to heal itself (regenerate) or receive a liver transplant. Defining the mechanisms by which the liver restores itself after injury is the primary goal of our laboratory. A better understanding of regeneration will allow us to design therapies that accelerate liver repair and may aid in the generation of liver cells for transplantation and for the production of artificial livers. These studies may also shed light on the process by which liver cancers develop.